Immune signatures predict development of autoimmune toxicity in patients with cancer treated with immune checkpoint inhibitors

Background: Immune checkpoint inhibitors (ICIs) are among the most promising treatment options for melanoma and non-small cell lung can-cer (NSCLC). While ICIs can induce effective anti-tumor responses, they may also drive serious immune-related adverse events (irAEs). Identi-fying biomarkers to predict which patients will suffer from irAEs would enable more accurate clinical risk-benefit analysis for ICI treatment and may also shed light on common or distinct mechanisms underpinning treatment success and irAEs. Methods: In this prospective multi-center study, we combined a multi-omics approach including unbiased single-cell profiling of over 300 pe-ripheral blood mononuclear cell (PBMC) samples and high-throughput proteomics analysis of over 500 serum samples to characterize the systemic immune compartment of patients with melanoma or NSCLC before and during treatment with ICIs.Findings: When we combined the parameters obtained from the multi-omics profiling of patient blood and serum, we identified potential predic-tive biomarkers for ICI-induced irAEs. Specifically, an early increase in CXCL9/CXCL10/CXCL11 and interferon -g (IFN-g) 1 to 2 weeks after the start of therapy are likely indicators of heightened risk of developing irAEs. In addition, an early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells is also likely to be associated with increased risk of irAEs.Conclusions: We suggest that the combination of these cellular and proteomic biomarkers may help to predict which patients are likely to benefit most from ICI therapy and those requiring intensive monitoring for irAEs.

Automated summary

In this study, a multi-omics approach was used to characterize the systemic immune compartment of melanoma or non-small cell lung cancer patients before and during immune checkpoint inhibitor (ICI) treatment. Potential predictive biomarkers for ICI-induced immune-related adverse events (irAEs) were identified, including early increase in CXCL9/CXCL10/CXCL11 and interferon-g (IFN-g) 1 to 2 weeks after treatment initiation, as well as early expansion of Ki-67+ regulatory T cells (Tregs) and Ki-67+ CD8+ T cells.